Resistance to blood flow in peripheral vascular beds strongly influences cardiovascular function and the status of perfused tissues. The primary determinants of flow resistance are vascular networ structure, vessel diameters, and flow properties of blood. It is proposed to develop quantitative theoretical models for structural adaptation of microvascular networks and for blood flow in microvessels. Structural adaptation (vascular remodeling) allows long-term adjustment of flow resistance to ensure adequate and efficient distribution of flow, and to respond to changing demands, as during growth or following injury. Abnormal structural adaptation occurs in hypertension and other diseases. Theoretical models have been developed to predict steady-state distributions of vessel internal diameters in microvascular networks, resulting from structural adaptation in response to hemodynamic and metabolic stimuli. These models will be extended to include consideration of (i) the time-course of diameter changes; (ii) changes in wall thickness and their relation to diameter changes; (iii) loss or gain of segments in vascular networks (Specific Aim 1). Model predictions will be compared with observations in several tissues, including rat mesentery, mouse and rat skeletal muscle, and mouse subcutaneous tissue (Specific Aim 2). Microvessel walls are lined by a relatively thick glycocalyx or endothelial surface layer (ESL). Previous theoretical models have shown how the ESL can substantially increase flow resistance in capillaries. Models will be developed to predict resistance to blood flow in microvessels larger than capillaries, including effects of the endothelial surface layer (Specific Aim 3). In all these studies, emphasis will be placed on comparing the results with experimental findings, and on examining their physiological implications in normal and abnormal states including hypertension. This will be facilitated by well-established and active collaborations with experimental physiologists.